World-wide public health surveys point to an increasing global health burden resulting from serious brain disorders, particularly mood-related disorders such as depression. The economic burden of depression alone is immense. Of the $83.1 billion spent in 2000 on the treatment of depression and related expenses, $26.1 billion (31 percent) were direct medical costs, $5.4 billion (7 percent) were suicide-related mortality costs, and $51.5 billion (62 percent) were workplace costs. Major depressive disorder is the leading cause of disability in the U.S. and other established market economies worldwide. Positron Emission Tomography (PET) imaging has become a powerful tool in mapping the distribution of proteins targeted by selectively binding radioligands in the healthy and diseased brain. As there is a growing body of evidence supporting norepinephrine's involvement in brain-related disorders such as depression, we have a unique opportunity to advance improved PET ligands targeted to the norepinephrine transporter (NET). The studies described in this research proposal are based upon preliminary and SAR data in-hand and involve the design and synthesis of improved NET- selective ligands, as well as the in vitro and in vivo testing of these compounds as PET imaging agents. Within the context of this grant, it is our intention to follow up on our exciting preliminary findings by conducting the following studies: 1. Using our best NET-selective lead structures, we will design and synthesize 15 new ligands for biological assay of monoamine transporter inhibitory activity. 2. Ligands with subnanomolar potency will be considered for radiolabeling, and suitable precursors will be prepared. 3. PET studies on radiolabeled compounds to investigate their pharmacokinetic properties as imaging agents will be carried out. 4. Promising PET imaging agents will be studied in cell toxicity and animal models during the second year.